Total submissions: 6
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV001035911 | SCV001199251 | uncertain significance | Fabry disease | 2023-12-31 | criteria provided, single submitter | clinical testing | This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 175 of the GLA protein (p.Asp175Glu). This variant is present in population databases (no rsID available, gnomAD 0.004%). This missense change has been observed in individuals with Fabry disease or hypertrophic cardiomyopathy (PMID: 23935525, 27532257; Invitae). ClinVar contains an entry for this variant (Variation ID: 835100). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GLA protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
Color Diagnostics, |
RCV001035911 | SCV001358881 | uncertain significance | Fabry disease | 2023-05-03 | criteria provided, single submitter | clinical testing | This missense variant replaces aspartic acid with glutamic acid at codon 175 of the GLA protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have shown that this variant results in a partially reduced enzyme activity (PMID: 31036492, 31367522, 32023956, 32531501). This variant has been reported in an individual affected with Fabry disease (PMID: 23935525) and in individuals affected with hypertrophic cardiomyopathy (PMID: 27532257, 32531501). This variant has been identified in 1/183473 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. |
Genome- |
RCV001035911 | SCV002054353 | uncertain significance | Fabry disease | 2021-07-15 | criteria provided, single submitter | clinical testing | |
Fulgent Genetics, |
RCV001035911 | SCV002815886 | uncertain significance | Fabry disease | 2021-12-03 | criteria provided, single submitter | clinical testing | |
Ambry Genetics | RCV003372939 | SCV004098463 | uncertain significance | Cardiovascular phenotype | 2023-09-05 | criteria provided, single submitter | clinical testing | The p.D175E variant (also known as c.525C>A), located in coding exon 3 of the GLA gene, results from a C to A substitution at nucleotide position 525. The aspartic acid at codon 175 is replaced by glutamic acid, an amino acid with highly similar properties. This alteration has been reported in hypertrophic cardiomyopathy (HCM) cohorts; however, clinical details were limited (Patel V et al. Heart, 2015 Jun;101:961-6; Walsh R et al. Genet Med, 2017 Feb;19:192-203; Azevedo O et al. Am Heart J, 2020 Aug;226:114-126). In vitro assays showed this alteration has >50% enzyme activity compared to wild-type (Lukas J et al. PLoS Genet, 2013 Aug;9:e1003632; Oommen S et al. Mol Genet Metab, 2019 May;127:74-85). Based on data from gnomAD, the A allele has an overall frequency of 0.0005% (1/183473) total alleles studied, with 0 hemizygote(s) observed. The highest observed frequency was 0.0036% (1/27429) of Latino alleles. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
Natera, |
RCV001035911 | SCV002081347 | uncertain significance | Fabry disease | 2020-09-17 | no assertion criteria provided | clinical testing |